Notice2023-09526
Identification, Assessment, and Control of Nitrosamine Drug Substance-Related Impurities in Human Drug Products; Establishment of a Public Docket; Request for Comments
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Published
May 4, 2023
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
The Food and Drug Administration (FDA, Agency, or we) is announcing the establishment of a docket to solicit public comments on the identification, assessment, and control of N-nitrosamine (nitrosamine) drug substance-related impurities (NDSRIs) that may be considered by the Agency in its regulation of these types of impurities in drug products. This notice identifies scientific and regulatory considerations regarding the identification, assessment, and control of NDSRIs, including areas that may benefit from collaborative efforts, and requests comments on these topics. This notice is not intended to communicate FDA's regulatory expectations on these issues but is instead intended to seek input from the public to inform scientific and/or regulatory approaches as appropriate.
Full Text
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[Federal Register Volume 88, Number 86 (Thursday, May 4, 2023)]
[Notices]
[Pages 28557-28562]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2023-09526]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2023-N-1585]
Identification, Assessment, and Control of Nitrosamine Drug
Substance-Related Impurities in Human Drug Products; Establishment of a
Public Docket; Request for Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice; establishment of a public docket; request for comments.
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SUMMARY: The Food and Drug Administration (FDA, Agency, or we) is
announcing the establishment of a docket to solicit public comments on
the identification, assessment, and control of N-nitrosamine
(nitrosamine) drug substance-related impurities (NDSRIs) that may be
considered by the Agency in its regulation of these types of impurities
in drug products. This notice identifies scientific and regulatory
considerations regarding the identification, assessment, and control of
NDSRIs, including areas that may benefit from collaborative efforts,
and requests comments on these topics. This notice is not intended to
communicate FDA's regulatory expectations on these issues but is
instead intended to seek input from the public to inform scientific
and/or regulatory approaches as appropriate.
DATES: Either electronic or written comments must be submitted by July
3, 2023.
ADDRESSES: You may submit comments as follows. Please note that late,
[[Page 28558]]
untimely filed comments will not be considered. The <a href="https://www.regulations.gov">https://www.regulations.gov</a> electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of July 3, 2023. Comments received
by mail/hand delivery/courier (for written/paper submissions) will be
considered timely if they are received on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
<bullet> Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
<bullet> For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked, and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-FDA-2023-N-1585 for ``Identification, Assessment, and Control of
Nitrosamine Drug Substance-Related Impurities in Human Drug Products;
Establishment of a Public Docket; Request for Comments.'' Received
comments, those filed in a timely manner (see ADDRESSES), will be
placed in the docket and, except for those submitted as ``Confidential
Submissions,'' publicly viewable at <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at
the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through
Friday, 240-402-7500.
<bullet> Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: Jason Bunting, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6366, Silver Spring, MD 20993-0002, 301-
796-1292, <a href="/cdn-cgi/l/email-protection#246e45574b4a0a46514a504d4a43644240450a4c4c570a434b52"><span class="__cf_email__" data-cfemail="3872594b5756165a4d564c51565f785e5c591650504b165f574e">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
I. Background
A. Nitrosamines, Including NDSRIs, in Human Drug Products
FDA has been investigating the presence of nitrosamine impurities
in certain drug products since June 2018. Nitrosamines are common in
water and foods, including cured and grilled meats, dairy products, and
vegetables. Nitrosamines may increase the risk of cancer if people are
exposed to them above acceptable levels. The acceptable intake (AI)
limit is a level that approximates an increased cancer risk of one
additional case in 100,000 people based on a conservative assumption of
daily exposure to the impurity or impurities over a lifetime (70 years)
(See FDA guidance for industry ``Control of Nitrosamine Impurities in
Human Drug Drugs'' (Nitrosamine Guidance) at 10, available at <a href="https://www.fda.gov/media/141720/download">https://www.fda.gov/media/141720/download</a> (Ref. 3).
When FDA was informed of the presence of an impurity identified as
N-nitrosodimethylamine (NDMA) in valsartan, an angiotensin II receptor
blocker (ARB), it began an investigation in which it determined that
numerous lots of valsartan and a few other ARB drug products from
different manufacturers contained unacceptable levels of nitrosamines.
The drug product manufacturers voluntarily recalled the affected
batches of these drug products, which led to a drug shortage in some of
the affected products. In addition, FDA evaluated processes used in
synthesis of the active pharmaceutical ingredient (API) and learned
that common synthetic pathways could also introduce other types of
nitrosamine impurities besides NDMA. FDA has continued to learn of the
existence of nitrosamine impurities such as NDMA in drug products in
several drug classes (see Ref. 3 at 2-3).
FDA originally published the Nitrosamine Guidance on September 3,
2020 (85 FR 55017), and updated the guidance on February 24, 2021 (Ref.
3). The guidance provides recommendations for industry regarding
nitrosamines, and NDSRIs are a subcategory of these impurities that
share structural similarity with the active pharmaceutical ingredient
in drug products. In the Nitrosamine Guidance, FDA recommends
manufacturers of APIs and drug products should take steps to detect and
prevent unacceptable levels of nitrosamine impurities in drug products,
or avoid their presence when feasible.\1\ Specifically, FDA
[[Page 28559]]
recommends a three-step process that manufacturers should take to
mitigate nitrosamine impurities in their products: (1) conduct risk
assessments for nitrosamines in their products; (2) conduct
confirmatory testing if risks are identified; and (3) report changes
implemented to prevent or reduce the presence of nitrosamine impurities
in drug products in approved and pending new drug applications (NDAs)
and abbreviated new drug applications (ANDAs). The Nitrosamine Guidance
describes some conditions that may introduce or create nitrosamine
impurities (a nitrosating reaction between secondary, tertiary, or
quaternary amines and nitrous acid (nitrite salts under acidic
conditions)) and provides FDA-recommended AI limits for six nitrosamine
impurities that could be present in drug products (see Ref. 3 at 10).
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\1\ The Nitrosamine Guidance notes that new drug application
(NDA) and abbreviated new drug application (ANDA) holders or
applicants, drug master file holders, and owners of marketed
products that are not the subject of approved NDAs or ANDAs (such as
compounded products or products marketed under an over-the-counter
drug monograph) who are not also the manufacturer of the drug
products and APIs should work with their contract manufacturers to
take the steps recommended in the Nitrosamine Guidance. This applies
to drug products currently available on the U.S. market as well as
those with pending applications. See Ref. 3 at 1, footnote 3.
Holders of biologics license applications for biological products
that contain chemically synthesized fragments or biologic-led
combination products that contain a drug constituent part also may
be affected.
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More recently, and often in response to the risk assessment
recommended in the Nitrosamine Guidance, FDA has received an increasing
number of reports of certain types of nitrosamine impurities that have
formed in drug products across multiple drug classes. These NDSRIs are
a class of nitrosamines sharing structural similarity to the API, and
thus, differ in certain respects from small molecule nitrosamine
impurities (i.e., nitrosamine impurities that do not share structural
similarity to the API, and are therefore, not considered NDSRIs)
identified in the Nitrosamine Guidance (see Ref. 3 at 10). NDSRIs can
be generated during manufacturing, or during the shelf-life storage
period of the drug product. They can also be generated during the
synthesis of the drug substance. In some cases, the root cause of NDSRI
formation has been attributed to nitrite impurities present in
excipients at parts-per-million amounts. Nitrite impurities have been
observed in a range of commonly used excipients (as well as water) and
may lead to the formation of NDSRIs in certain drug products. In
general, there is a risk of generating nitrosamine impurities when
nitrites are in the presence of secondary, tertiary, or quaternary
amines. Secondary or tertiary amines are known to be part of the
chemical structure of several hundred APIs. Accordingly, depending on
the formulation and manufacturing process for the drug product, as well
as ongoing oversight of the quality of materials produced by suppliers,
there may be a risk of nitrosamine formation in a substantial number of
drug products.
In November 2021, FDA alerted the public regarding the presence of
NDSRIs and indicated that manufacturers could ascertain the presence of
NDSRIs using the same three-step process identified in the Nitrosamine
Guidance (Ref. 4). As discussed further below, FDA also conveyed
possible mitigation strategies, and encouraged applicants to develop
control strategies or design approaches to reduce NDSRIs to acceptable
levels or eliminate them (where feasible).
NDSRIs present unique scientific and regulatory challenges for FDA
because each NDSRI is unique to the API, and there is limited compound-
specific data that is available to inform safety assessments.
Additionally, design of validated test methods for identification of
NDSRIs and modification of existing test methods for assessment of
their mutagenic potential may raise novel scientific considerations.
B. Safety Assessments of the Potential for Mutagenic and Carcinogenic
Risk
In the Nitrosamine Guidance, FDA recognizes that nitrosamine
compounds are potent genotoxic agents in several animal species, and
some have been classified as probable or possible human carcinogens by
the World Health Organization's International Agency for Research on
Cancer (see Ref. 3 at 5). The framework for identifying, categorizing,
qualifying and controlling DNA reactive (mutagenic) impurities to limit
potential carcinogenic risk is provided in FDA and International
Council for Harmonisation guidance for industry entitled ``M7(R1)
Assessment and Control of DNA Reactive (Mutagenic) Impurities in
Pharmaceuticals To Limit Potential Carcinogenic Risk'' (ICH M7(R1)
Guidance), available at <a href="https://www.fda.gov/media/85885/download">https://www.fda.gov/media/85885/download</a> (Ref.
5). (The ICH M7(R1) Guidance was prepared under the auspices of the
ICH). Nitrosamines as a structural group are referred to as ``cohort of
concern'' compounds in the ICH M7(R1) Guidance because of their
classification as high-potency mutagenic carcinogens. It is currently
unknown if all or some NDSRIs are associated with this classification.
The ICH M7(R1) Guidance provides guidance to derive AI limits for
some chemicals that are considered mutagens and carcinogens and are
also commonly used in the synthesis of pharmaceuticals or are useful
examples to illustrate the principles for deriving compound-specific
intakes otherwise described in the ICH M7(R1) Guidance (see the Federal
Register notice issued March 14, 2018 (83 FR 11210). Specifically, the
ICH M7(R1) Guidance recommends applicants use a hazard assessment,
which involves an initial analysis of actual and potential impurities
by conducting database and literature searches for carcinogenicity and
bacterial mutagenicity data, to classify impurities into one of five
classes and proposes action for control based on the resulting class
(with Class 1 being known mutagenic carcinogens and Class 5 being
impurities with no structural alerts,\2\ or alerting structure with
sufficient data to demonstrate lack of mutagenicity or carcinogenicity)
(see Ref. 5 at 10). If data are not available for such a
classification, a computational toxicology assessment should be
conducted using two (quantitative) structure-activity relationship
((Q)SAR) methodologies that can predict the outcome of a bacterial
mutagenicity test (see Ref. 5 at 9-10). In the ICH M7(R1) Guidance, FDA
recommends that impurities for each class be controlled at specified
limits; for example, it recommends Class 1 impurities be controlled at
or below compound-specific acceptable limits, and Class 5 impurities be
controlled as non-mutagenic impurities (see Ref. 5 at 10).
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\2\ The ICH M7(R1) Guidance defines a structural alert in the
context of the guidance as ``a chemical grouping or molecular (sub)
structure which is associated with mutagenicity'' (Ref. 5 at 129).
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1. Assessment of Potential Mutagenicity and Carcinogenicity
FDA typically requests that applicants assess the potential for an
impurity to be mutagenic by conducting a standard in vitro bacterial
reverse mutation test (Ames test). If this in vitro mutagenicity
testing is negative for a nitrosamine impurity, FDA has requested
further testing because standard methods used for the Ames test may not
be adequate to characterize the mutagenic potential of nitrosamines, in
some cases producing negative results with known mutagenic
nitrosamines. Information in published scientific literature suggests
that some Ames tests (e.g., those conducted with rat S9) may not be
sensitive enough to assess the mutagenicity of nitrosamine compounds
because of species-specific differences in metabolic activation of
potential mutagens. Additionally, there is limited experience on the
sensitivity of these tests for NDSRIs, which are more complex
structures than the more commonly identified nitrosamines in the
Nitrosamine Guidance. Therefore, FDA's National Center for
Toxicological Research has been testing different conditions to develop
an enhanced
[[Page 28560]]
Ames test that is intended to provide a more reliable assessment of
potential mutagenicity in small molecule nitrosamine impurities and
NDSRIs.
In some circumstances in which the results of an enhanced Ames test
are negative, the mutagenic potential of the impurity was further
assessed in an in vivo transgenic gene mutation test to confirm the in
vitro findings. If further in vivo testing is to be conducted, the
selection of the in vivo mutagenicity tests should be scientifically
justified based on knowledge of the mechanism of action of the impurity
and expected target tissue exposure (see Ref. 5 at 11 and at (Note 3)
21-22). To avoid potentially duplicative nonclinical in vitro or in
vivo testing of NDSRIs by manufacturers of drug products containing the
drug substance, FDA is interested in exploring the feasibility of
collaborative efforts among applicants and manufacturers of affected
drug products.
2. Computational Toxicology
In general, (Q)SAR models are accepted as a scientific tool for
predicting and classifying the biological activities of untested
chemicals. A computational toxicology assessment using (Q)SAR
methodologies can predict, with acceptable confidence, the outcome of
an Ames test by using two complementary, validated modeling
methodologies (statistical-based and expert rule-based) and can be used
to classify an impurity as mutagenic or non-mutagenic (see Ref. 5 at
10). The methodology uses statistical and/or manual approaches to
correlate and rationalize variations in the biological activity of a
series of chemicals with variations in their molecular structures,
which are often represented by a set of quantities commonly known as
``structural descriptors.'' Because (Q)SAR models can generate a
prediction of a chemical's biological activity from structural
descriptors more rapidly than in vitro or in vivo testing can be
conducted, they provide a means to efficiently assess nitrosamine
toxicity when experimental data are unavailable. However, the
predictive performance of (Q)SAR models depends on many factors,
particularly on the quality of biological training data, descriptor
selection, and modeling algorithm. Therefore, FDA has been working with
model developers and stakeholders to advance predictive toxicology,
with a focus on the use of (Q)SAR methodologies in assessing potential
mutagenicity and carcinogenicity of NDSRIs.
3. Determining AI Limits for NDSRIs
A recommended AI limit is based on a safety assessment that
includes evaluation of the mutagenic and carcinogenic potential of the
impurity and represents the level at or below which FDA has determined
that the impurity or impurities would not pose a safety concern for
patients taking the drug product. The AI limit is a level that
approximates an increased cancer risk of 1:100,000 based on a
conservative assumption of daily exposure to the impurity or impurities
over a lifetime (70 years) (see Ref. 3 at 10 and Appendix B ``FDA
Determination of Acceptable Intake Limits''). The AI limit is generally
described in nanograms per day, and each applicant establishes
specifications to control for the level of impurity or impurities in
their drug products (in parts per million) based on the maximum daily
dose of the drug product under the labeled conditions of use. Once a
recommended AI limit has been established, applicants and manufacturers
would generally be expected to control impurities within the
recommended AI limit (see Ref. 3 at 14, 15). Applicants or
manufacturers should contact FDA regarding drug products with
unacceptable levels of nitrosamine impurities that are already in
distribution (see Ref. 3 at 14, 15). Additionally, applicants and
manufacturers may need to modify the manufacturing processes or
reformulate their drug products to control impurities within the
recommended AI limit \3\ or submit additional testing to FDA that would
demonstrate the applicant's proposed limit is safe.\4\
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\3\ For recommendations to API manufacturers and drug
manufacturers see Ref. 3 at 11-15.
\4\ See, e.g., generally Ref. 5, which provides a framework for
the identification, categorization, qualification, and control of
mutagenic impurities to limit potential carcinogenic risk, at 4 and
``Table 1: Impurities Classification With Respect to Mutagenic and
Carcinogenic Potential and Resulting Control Actions,'' at 10. The
guidance further explains that if an impurity has a positive
bacterial mutagenicity result and cannot be controlled at an
appropriate acceptable limit, then it may be recommended that the
impurity be tested in an in vivo gene mutation assay, which may
support recommending a compound-specific impurity limit (see Ref. 5
at 11).
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Calculating a recommended AI limit for NDSRIs is often more
challenging than calculating recommended AI limits for small molecule
nitrosamines, primarily because NDSRIs are unique to each API and there
is usually limited or no existing safety data (e.g., rodent
carcinogenicity data) on NDSRIs (see also Ref. 5 at 12 and note 4 on
calculating a compound-specific AI limit). FDA has published
recommended AI limits for a limited number of NDSRIs, but unlike more
commonly known nitrosamines (such as those identified in the
Nitrosamine Guidance), a recommended AI limit has not yet been
determined for most NDSRIs.
If mutagenic potential is identified through toxicological testing
or computational toxicology models, FDA and applicants have used (Q)SAR
methods to identify and select a data-rich surrogate that is similar in
structure and reactivity to the data-poor NDSRI to generate an estimate
of carcinogenic potency from which an AI limit can be determined. In
this scenario, surrogates are compounds containing an N-nitroso
structural alert in the same chemical environment as an NDSRI and for
which robust carcinogenicity data are available (see Ref. 5 at 11-12).
The rationale for the choice of surrogate (similar in structure and
reactivity) is significant because test data from the identified
surrogate is then used to generate an estimate, either quantitatively
or qualitatively, for the data-poor compound (commonly referred to as a
``read-across analysis'').
The nitrosamine structural alert environment is an important factor
when selecting appropriate reference compounds for a read-across
analysis and may include consideration of the degree of substitution,
steric bulk, electronic influences, potential for metabolic activation,
stability/reactivity of the resulting metabolites, and overall
molecular weight. Additionally, the quality of carcinogenicity studies
in the published scientific literature can be quite variable; however,
use of less robust data can sometimes be considered acceptable when no
more complete data exist, given the highly conservative nature of the
risk assessment (see Ref. 5 at 36).
C. FDA's Ongoing Work on Nitrosamine Risk Assessment and Mitigation
Since the issuance of the Nitrosamine Guidance, FDA has continued
to work to better understand the root causes of nitrosamines, develop
mitigation strategies that can eliminate or minimize the presence of
nitrosamines in drug products, and improve approaches to risk
assessment (mutagenicity and carcinogenicity) of NDSRIs in drug
substances and drug products that can inform recommended AI limits.
As FDA learned more about NDSRI formation and received increasing
numbers of reports from industry on the presence of NDSRIs, the Agency
identified on its web page two examples of mitigation strategies
related to formulation design to assist
[[Page 28561]]
manufacturers in reducing the levels of NDSRIs in drug products. One
mitigation strategy was derived from published literature reports that
demonstrated that commonly used antioxidants, such as ascorbic acid
(vitamin C) or alpha-tocopherol (vitamin E), inhibit the formation of
nitrosamines in vivo, based on data from human gastric fluid in vitro
studies (see Ref. 4). FDA advised that recent work preliminarily
demonstrated that the addition of these antioxidants to formulations
may significantly inhibit the formation of NDSRIs in drug products. FDA
also presented a second possible mitigation strategy related to
formulation design based on the fact that the formation of nitrosamines
typically occurs under acidic conditions, whereas, in a neutral or
basic environment, the kinetics of these reactions are significantly
reduced (Ref. 4). FDA has encouraged manufacturers to consider these as
well as other innovative strategies to reduce the formation of NDSRIs
to acceptable levels in drug products.
D. Regulatory Challenges
The identification of a new impurity, such as an NDSRI, may have
implications for a cohort of pending or approved NDAs (including
applications submitted pursuant to section 505(b)(2) of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 355(b)(2))) and ANDAs and also
creates unique challenges from a regulatory perspective. For example, a
generic drug applicant typically may qualify the level of an impurity
that does not have a limit in an applicable U.S. Pharmacopeia monograph
or that does not otherwise have a recommended AI limit (e.g., as
described in applicable guidance) by comparing its proposed product to
the observed amounts of the impurity in the previously approved drug
product (the reference listed drug) on which it relies for approval
(see Refs. 1 and 2). This approach reflects that identification and
evaluation of certain impurities to establish the biological safety of
the impurity at the level(s) present in the API or drug product
typically occurs before approval of the NDA for the reference listed
drug, and subsequently, ANDA applicants can conduct comparative testing
of their products and the reference listed drug to qualify impurities.
However, challenges arise when each applicant in a cohort of pending or
approved NDAs (including section 505(b)(2) applications) and ANDAs
concurrently conducts risk assessments for the presence of an NDSRI in
their drug products and, if present, develops data to support an AI
limit and specifications for controlling the impurity in their drug
products.
Moreover, information on impurities in drug products that may
reveal an aspect of an applicant's manufacturing method or process
generally has been protected from public disclosure, unless such
information has been previously disclosed by the applicant or is
otherwise publicly available. Thus, FDA may be limited in the impurity
information that it can disclose to facilitate efficient evaluation of
other products and to inform applicants of actions they can take to
mitigate nitrosamine risk. In addition, there are considerations that
may constrain FDA's ability to disclose certain information provided by
an applicant in FDA's evaluation of other applicants' submissions to
FDA, which can lead to potentially duplicative nonclinical tests (which
may include animal testing) to characterize the risk and inform a
recommended AI limit. This can be a significant concern when a newly
identified NDSRI may have implications for a cohort of pending or
approved marketing applications. For example, there are circumstances
in which potential constraints regarding disclosure could hamper FDA's
ability to quickly and publicly identify a compound-specific
recommended AI limit for an NDSRI that may be applicable to all drug
products that contain the API. Potential constraints related to
disclosure of certain information regarding impurities could also lead
to delays in providing applicants, including follow-on and generic drug
products, with information to develop drug products with acceptable
impurity profiles. Additionally, uncertainty about the presence and/or
acceptability of the level of an impurity raises additional regulatory
challenges and could lead to some applicants conducting unnecessary
studies or even discontinuing drug products from the market,
potentially resulting in drug shortages. These difficulties can impact
patient access to medications, including drugs that are considered
medically necessary.
To avoid these potential issues, at times, FDA generates and makes
publicly available information or research to support the development
of recommended AI limits by conducting additional studies, developing
enhanced Ames testing, or using (Q)SAR methodology to identify
appropriate surrogates from which read-across can be used to estimate
carcinogenic potency. Applicants can use this FDA-generated information
to set individual drug product specifications. The absence of publicly
available data to support a recommended AI limit for an NDSRI can
result in potentially duplicative studies to support a recommended AI
limit. Moreover, if in vivo animal studies are necessary to assess the
risk of a particular NDSRI, such potentially duplicative testing may
not align with FDA's policy to replace, reduce, and refine the use of
animals for safety testing (the 3R principles), where possible (see,
e.g., Ref. 6 at 1).
E. Collaborative Efforts To Develop NDSRI Data
FDA has encouraged collaborative efforts by applicants and other
stakeholders, together with the Agency as appropriate, to help address
the challenges presented by NDSRIs. FDA also has collaborated with
international regulatory agencies through the Nitrosamines
International Strategic Group and the Nitrosamines International
Technical Working Group, which were formed to share scientific
knowledge and current thinking on technical safety and quality topics
related to nitrosamines and to promote technical convergence among
member jurisdictions, where possible. In other areas, FDA is
collaborating on multi-laboratory projects being organized by the
Health and Environmental Sciences Institute's Genetic Toxicology
Technical Committee that include industry stakeholders and regulatory
agencies such as Health Canada and European Medicines Agency.
Additionally, FDA has been actively engaged with model developers and
stakeholders to advance predictive toxicology with a focus on the use
of (Q)SAR methodologies in assessing potential mutagenicity and
carcinogenicity of NDSRIs.
Development of laboratory test methods to identify NDSRIs is an
area that could benefit from collaborative efforts. In the Nitrosamine
Guidance, FDA encourages manufacturers or laboratories to make
validated test methods publicly available (e.g., by posting on the
method developer's website) to facilitate faster testing of other
similar drug products. FDA also accepts requests to post privately
developed methods on FDA's website if FDA's review of the method
protocol finds it scientifically sound and if the method owner provides
written authorization for posting by FDA (see Ref. 3 at 11, footnote
37). As another example, a positive bacterial mutagenicity result may
warrant an additional in vivo gene mutation assay, typically a
transgenic mutation assay, to understand the relevance of the bacterial
mutagenicity test under in vivo conditions (see Ref. 5 at 11 and (Note
3)
[[Page 28562]]
(identifying the transgenic mutation assay as appropriate for followup
for any positive bacterial mutagenicity test as opposed to other tests,
which are recommended under more limited circumstances). When such in
vivo testing is warranted, industry collaboration on the testing to
develop robust data and share results among themselves could enhance
scientific analyses and could facilitate regulatory decision-making.
Similarly, we have encouraged applicants to publish scientific research
and test results to further scientific knowledge on NDSRIs and
facilitate regulatory decision-making, as appropriate.
II. Issues for Consideration and Request for Comments
FDA is requesting comments from the public regarding the
identification, assessment, and control of NDSRIs in drug product
development and regulatory review to provide interested parties an
opportunity to comment on scientific and regulatory considerations,
including areas that may benefit from collaborative efforts. FDA is
also interested in any challenges preventing industry from identifying,
assessing, and controlling NDSRIs that may assist FDA in its analysis.
The questions posed below are not meant to be exhaustive. FDA is
interested in other pertinent information that stakeholders would like
to provide on issues and challenges related to addressing NDSRIs. FDA
is particularly interested in comments on the following topics:
A. General Questions
1. What additional topics related to the evaluation of nitrosamines
should be a priority for the Agency to address through guidance
documents?
2. What factors should FDA consider in prioritizing its evaluation
of NDSRIs on a compound-specific basis?
3. What additional mitigation strategies should be considered for
reducing NDSRI formation or eliminating these impurities (where
feasible)?
B. NDSRI Risk Assessment
1. What scientific and technical factors should FDA consider in
developing best practices for conducting testing for NDSRIs (e.g., Ames
test, enhanced Ames test, followup in vitro mutagenicity, in vivo
transgenic gene mutation test) in support of establishing AI limits?
a. Are there other tests recommended for assessing mutagenic
potential of NDSRIs, and how supportable are these methods?
b. Would ``short-term'' carcinogenicity testing (e.g., 6-month
transgenic mouse model) be informative to evaluate the risk associated
with NDSRIs?
c. If so, what are the advantages and disadvantages to such
testing?
d. Are there other types of studies that may further inform FDA
about the risk associated with NDSRI (e.g., in vitro/in vivo
metabolism, DNA biomarkers, identification of reactive intermediates)?
2. FDA recommended in the Nitrosamine Guidance that confirmatory
testing of drug products and submission of required changes in drug
applications be concluded on or before October 1, 2023 (see Ref. 3 at
17). Would an extension of the recommended timeline for submission of
changes in drug applications as described in the guidance to June 1,
2024, allow for additional assessment of NDSRIs and enable
collaborative efforts among affected applicants? How can FDA further
support manufacturers' efforts toward completion of confirmatory
testing?
C. Collaborative Efforts To Develop NDSRI Data and Establish and
Implement Recommended AI Limits
1. How can FDA facilitate collaborative efforts to generate
reliable compound-specific data on NDSRIs and reduce the need for
additional and potentially duplicative testing?
2. Are there obstacles that industry has encountered when engaging
in collaborative efforts that could allow companies to share data to
assess the safety of NDSRIs, particularly with the intent of reducing
redundant testing and integrating the 3R principles? Such examples of
collaboration may include enhancing (Q)SAR methods and models,
conducting in vitro mutagenicity testing and/or in vivo transgenic gene
mutation tests. If there are such obstacles, are there ways that FDA
could facilitate collaboration?
D. Establishing and Implementing Recommended AI Limits and Access to
Medications
1. In implementing recommendations for controlling nitrosamines,
including NDSRIs, have manufacturers or suppliers experienced
difficulties with meeting recommended AI limits that has led to
discontinuation of manufacturing or distribution?
III. References
The following references are on display at the Dockets Management
Staff (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also
available electronically at <a href="https://www.regulations.gov">https://www.regulations.gov</a>. FDA has
verified the website addresses, as of the date this document publishes
in the Federal Register, but websites are subject to change over time.
1. Food and Drug Administration (FDA) guidance for industry
``ANDAs: Impurities in Drug Substances,'' June 2009, available at
<a href="https://www.regulations.gov/document/FDA-1998-D-0021-0008">https://www.regulations.gov/document/FDA-1998-D-0021-0008</a>.
2. FDA guidance for industry ``ANDAs: Impurities in Drug
Products,'' November 2010, available at <a href="https://www.fda.gov/media/71351/download">https://www.fda.gov/media/71351/download</a>.
3. FDA guidance for industry ``Control of Nitrosamine Impurities
in Human Drugs,'' February 2021, available at <a href="https://www.fda.gov/media/141720/download">https://www.fda.gov/media/141720/download</a>.
4. FDA, ``Updates on Possible Mitigation Strategies To Reduce
the Risk of Nitrosamine Drug Substance-Related Impurities in Drug
Products,'' available at <a href="https://www.fda.gov/drugs/drug-safety-and-availability/updates-possible-mitigation-strategies-reduce-risk-nitrosamine-drug-substance-related-impurities">https://www.fda.gov/drugs/drug-safety-and-availability/updates-possible-mitigation-strategies-reduce-risk-nitrosamine-drug-substance-related-impurities</a>. Last accessed April
14, 2023.
5. FDA and International Council for Harmonisation guidance for
industry ``M7(R1) Assessment and Control of DNA Reactive (Mutagenic)
Impurities in Pharmaceuticals To Limit Potential Carcinogenic
Risk,'' March 2018, available at <a href="https://www.fda.gov/media/85885/download">https://www.fda.gov/media/85885/download</a>.
6. FDA and International Council for Harmonisation guidance for
industry, ``M3(R2) Nonclinical Safety Studies for the Conduct of
Human Clinical Trials and Marketing Authorization for
Pharmaceuticals'' January 2010, available at <a href="https://www.fda.gov/media/71542/download">https://www.fda.gov/media/71542/download</a>.
Dated: May 1, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-09526 Filed 5-3-23; 8:45 am]
BILLING CODE 4164-01-P
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